Isoxazoline parasiticide formulations and methods for treating blepharitis

ABSTRACT

Disclosed herein are methods for treating or preventing ophthalmic and dermatologic conditions in a patient, including ocular surface conditions such as blepharitis. The methods can include topically administering directly to an ocular surface of one or more eyes of a patient in need of treatment thereof an effective amount of an isoxazoline parasiticide, formamidine parasiticide, or other active ingredient, formulated into an ophthalmic composition, the ophthalmic composition further comprising a pharmaceutically acceptable vehicle. Compositions are also disclosed.

PRIORITY CLAIM

This application claims the benefit under 35 U.S.C. § 120 as acontinuation application of U.S. application Ser. No. 17/099,531 filedon Nov. 16, 2020, which in turn claims the benefit under 36 U.S.C. § 120as a continuation of U.S. application Ser. No. 16/221,390 filed on Dec.14, 2018, which in turn claims the benefit under 35 U.S.C. § 119(e) as anonprovisional application of each of U.S. Prov. App. Nos. 62/599,213filed on Dec. 15, 2017, 62/615,855 filed on Jan. 10, 2018, 62/626,612filed on Feb. 5, 2018, 62/689,787 filed on Jun. 25, 2018, and 62/746,498filed on Oct. 16, 2018. Each of the foregoing applications are herebyincorporated by reference in their entireties.

BACKGROUND

Blepharitis, or inflammation of the eyelids, is a common, often chroniccondition that can be challenging to treat, and affect any age group.Blepharitis can be both anterior (outer surface of the eyelid affected,where the eyelashes are attached) and/or posterior (inner surface of theeyelid affected). Blepharitis can be associated with systemic diseasesincluding rosacea and seborrheic dermatitis, and be related to otherophthalmic diseases including chalazion, conjunctivitis, keratitis, anddry eyes.

Demodex folliculorum and Demodex brevis are microscopic, obligate,elongated mites that are the most common permanent intracutaneousparasites inhabiting the hair follicles and sebaceous glands of humansand animals. A total of 65 Demodex species have been described,parasitizing 11 orders of mammals and belonging to the familyDemodicidae of the order Acarina, class Arachnida. Mating takes place inthe follicle opening and eggs are laid inside the hair follicles orsebaceous glands. The six-legged larvae hatch after 3-4 days, and thelarvae develop into adults in about 7 days. Demodex has a life cycle ofabout 14 days. The total lifespan of a Demodex mite is several weeks.The dead mites decompose inside the hair follicles or sebaceous glands.

Demodex can be found on the face, including cheeks, nose, chin,forehead, temples, eye lashes, brows, and also on the scalp, neck, andears. Other seborrheic locations such as naso-labial folds, peri-orbitalareas, and less commonly upper and medial region of chest and back canalso be infested. Demodex may also be found on the penis, mons veneris,buttocks, and in the ectopic sebaceous glands in the buccal mucosa. Insome cases, a mite density of greater than 5 mites/cm² in thepilo-sebaceous unit or 5 or more mites per follicle correlates with aDemodex infestation.

Among a wide range of reported species, only two, Demodex folliculorumand Demodex brevis, are found to parasitize the human body surface.Demodex folliculorum has been found for example on eyelash follicles,while Demodex brevis has been found, for example, proximate meibomian(tarsal) glands around the eye and sebaceous glands of the skin.Meibomian glands are a holocrine type of exocrine glands, at the rim ofthe eyelids inside the tarsal plate, responsible for the supply ofmeibum, an oily substance that prevents evaporation of the eye's tearfilm. Meibum prevents tear spillage onto the cheek, trapping tearsbetween the oiled edge and the eyeball, and makes the closed lidsairtight. There are approximately 50 glands on the upper eyelids and 25glands on the lower eyelids. Symbiotic bacteria on the mites also cancontribute to pathology. Increased sebum secretion and an increasednumber of sebaceous glands can provide a favorable habitat for themites. While some level of Demodex can be asymptomatic, multiplicationof Demodex mites to high densities, and/or a concurrent immune imbalanceusually leads to skin damage. A growing body of literature implicatesDemodex mites in anterior and posterior blepharitis. For example,Demodex has been implicated in 45% of blepharitis cases. It has beenestimated that the prevalence of ocular surface disease is about 30million patients; 19 million of which have Meibomian glanddysfunction/posterior blepharitis; 9 million with Demodex infestation,and 4 million with clear signs of Demodex. Blepharitis is a significantdiagnosis, with no approved therapy currently in the US. Safe,efficacious therapies to treat blepharitis and other ophthalmic anddermatologic conditions are needed.

SUMMARY

In some embodiments, disclosed herein are topical therapeutic agents,including but not limited to topical pharmaceutical agents including oneor more isoxazoline parasiticides, formamidine parasiticides,phenylpyrazole parasiticides, drugs generally used for the treatment ofAlzheimer's disease (e.g., galantamine and others), and other agents forthe treatment of various ophthalmic and dermatologic conditions.

In some configurations, disclosed herein is a method for treatingblepharitis in a patient, comprising topically administering directly toan ocular surface of one or more eyes of a patient in need of treatmentthereof an effective amount of an isoxazoline parasiticide, formulatedinto an ophthalmic composition, the ophthalmic composition furthercomprising a pharmaceutically acceptable vehicle.

In some configurations, the ophthalmic composition is sterile andnon-irritating to the eye.

In some configurations, the isoxazoline parasiticide can be the soleactive ingredient of the ophthalmic composition.

In some configurations, from about 0.01% to about 1% of the isoxazolineparasiticide with respect to the total weight of the composition isadministered.

In some configurations, about 0.03% by weight of the isoxazolineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, about 0.10% by weight of the isoxazolineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, the ophthalmic composition comprises an eyedrop.

In some configurations, the ophthalmic composition does not include anyessential oils.

In some configurations, the isoxazoline parasiticide is selected fromthe group consisting of: fluralaner, sarolaner, lotilaner, afoxolaner,and fluxametamide.

In some configurations, the ocular surface comprises at least one of theconjunctiva or cornea of the one or more eyes of the patient.

In some configurations, the ophthalmic composition comprises apolysorbate.

In some configurations, disclosed herein is a method for treatingblepharitis in a patient, comprising topically administering directly toone or more of the eye, eyelids, or eyelashes of a patient in need oftreatment thereof an effective amount of an isoxazoline parasiticide,formulated into an ophthalmic composition further comprising apharmaceutically acceptable vehicle, wherein the ophthalmic compositionis sterile and non-irritating to the eye, wherein the isoxazolineparasiticide is the sole active ingredient of the ophthalmiccomposition.

In some configurations, the patient's eyes are closed upon topicallyadministering the ophthalmic composition, such that the compositioncontacts orifices of Meibomian glands of the patient and outside ofeyelid margins of the patient.

In some configurations, the method further comprises spreading thecomposition onto the eyelashes and follicles of the eyelashes.

In some configurations, the method further comprises spreading thecomposition onto the eyelashes and follicles of the eyelashes with anapplicator.

In some configurations, from about 0.001% to about 1% of the isoxazolineparasiticide is administered.

In some configurations, from about 0.001% to about 1% of the isoxazolineparasiticide is administered.

In some configurations, the method further comprises topicallyadministering the ophthalmic composition at least once daily for atleast about 2 weeks.

In some configurations, the method further comprises topicallyadministering the ophthalmic composition at least once daily for atleast about 4 weeks.

In some configurations, disclosed herein is a method for treating anocular Demodex infestation in a patient, comprising topicallyadministering directly to one or more of the eyes, eyelids, or eyelashesof one or more eyes of a patient in need of treatment thereof, aneffective amount of an isoxazoline parasiticide, formulated into anophthalmic composition further comprising a pharmaceutically acceptablevehicle, wherein the ophthalmic composition is sterile andnon-irritating to the eye, wherein the isoxazoline parasiticide is thesole active ingredient of the ophthalmic composition.

In some configurations, the method further comprises receiving a firstassessment of a quantity of Demodex mites on an anatomical structure ofthe patient, and topically administering the ophthalmic composition ifthe quantity of Demodex mites is greater than a predetermined value.

In some configurations, the ophthalmic formulation causes an abdomen andtail of Demodex mites on the patient to stop moving more quicklyrelative to a cephalothorax of the Demodex mites.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea, comprising topically applying isoxazolineparasiticides proximate one or more eyelashes, the topically applyingtherapeutically effective to preferentially be absorbed by a body of theDemodex mite with respect to ingestion by the Demodex mite sufficient tocause reduced movement of the body of the Demodex mite with respect to ahead of the Demodex mite, the method sufficient to reduce or eliminateDemodex mites proximate the eyelashes, resulting in improvement of themanifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a topical ophthalmicformulation for treating blepharitis in a patient, comprising aneffective amount of an isoxazoline parasiticide and a pharmaceuticallyacceptable vehicle, wherein the ophthalmic composition is sterile andnon-irritating to the eye, wherein the isoxazoline parasiticide is thesole active ingredient of the ophthalmic composition.

In some configurations, from about 0.01% to about 1% of the isoxazolineparasiticide with respect to the total weight of the composition isadministered.

In some configurations, about 0.03% by weight of the isoxazolineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, about 0.10% by weight of the isoxazolineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, the ophthalmic composition comprises an eyedrop.

In some configurations, the ophthalmic composition does not include anyessential oils.

In some configurations, the isoxazoline parasiticide is selected fromthe group consisting of: fluralaner, sarolaner, lotilaner, afoxolaner,and fluxametamide.

In some configurations, disclosed herein is a topical formulation foruse in treating an ocular surface disease, comprising: an isoxazolineparasiticide; at least one of Pemulen and HPMC; polysorbate 80;glycerin; a buffering agent; and lauralkonium chloride, wherein theformulation is therapeutically effective to reduce or eliminate Demodexmites proximate the eyelashes, resulting in improvement of themanifestations of blepharitis and/or rosacea.

In some configurations, the formulation is for use in treatingblepharitis.

In some configurations, the formulation is for use in treating anteriorblepharitis.

In some configurations, the formulation is for use in treating posteriorblepharitis.

In some configurations, the formulation is for use in treating ocularrosacea.

In some configurations, disclosed herein is a method for treatingblepharitis in a patient, comprising topically administering directly toan ocular surface of one or more eyes of a patient in need of treatmentthereof an effective amount of an formamidine parasiticide, formulatedinto an ophthalmic composition, the ophthalmic composition furthercomprising a pharmaceutically acceptable vehicle, wherein the ophthalmiccomposition is sterile and non-irritating to the eye, wherein theformamidine parasiticide is the sole active ingredient of the ophthalmiccomposition.

In some configurations, from about 0.01% to about 1% of the formamidineparasiticide with respect to the total weight of the composition isadministered.

In some configurations, about 0.03% by weight of the formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, about 0.10% by weight of the formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, the ophthalmic composition comprises an eyedrop.

In some configurations, the ophthalmic composition comprises an ointmentor cream.

In some configurations, the ophthalmic composition does not include anyessential oils.

In some configurations, the formamidine parasiticide is selected fromthe group consisting of: amitraz,N-(2,4-Dimethylphenyl)-N-methyformamidine (DPMF), and2,4-dimethylanaline.

In some configurations, the ocular surface comprises at least one of theconjunctiva or cornea of the one or more eyes of the patient.

In some configurations, the ophthalmic composition comprises apolysorbate.

In some configurations, disclosed herein is a method for treatingblepharitis in a patient, comprising topically administering directly toone or more of the eye, eyelids, or eyelashes of a patient in need oftreatment thereof an effective amount of an formamidine parasiticide,formulated into an ophthalmic composition further comprising apharmaceutically acceptable vehicle, wherein the ophthalmic compositionis sterile and non-irritating to the eye, wherein the formamidineparasiticide is the sole active ingredient of the ophthalmiccomposition.

In some configurations, the patient's eyes are closed upon topicallyadministering the ophthalmic composition, such that the compositioncontacts orifices of meibomian glands of the patient and outside ofeyelid margins of the patient.

In some configurations, the method further comprises spreading thecomposition onto the eyelashes and follicles of the eyelashes.

In some configurations, the method further comprises spreading thecomposition onto the eyelashes and follicles of the eyelashes with anapplicator.

In some configurations, from about 0.001% to about 1% of the formamidineparasiticide is administered.

In some configurations, from about 0.001% to about 1% of the formamidineparasiticide is administered.

In some configurations, the method further comprises topicallyadministering the ophthalmic composition at least once daily for atleast about 2 weeks.

In some configurations, the method further comprises topicallyadministering the ophthalmic composition at least once daily for atleast about 4 weeks.

In some configurations, disclosed herein is a method for treating anocular Demodex infestation in a patient, comprising topicallyadministering directly to one or more of the eyes, eyelids, or eyelashesof one or more eyes of a patient in need of treatment thereof, aneffective amount of an formamidine parasiticide, formulated into anophthalmic composition further comprising a pharmaceutically acceptablevehicle, wherein the ophthalmic composition is sterile andnon-irritating to the eye, wherein the formamidine parasiticide is thesole active ingredient of the ophthalmic composition.

In some configurations, the method further comprises receiving a firstassessment of a quantity of Demodex mites on an anatomical structure ofthe patient, and topically administering the ophthalmic composition ifthe quantity of Demodex mites is greater than a predetermined value.

In some configurations, the ophthalmic formulation causes an abdomen andtail of Demodex mites on the patient to stop moving more quicklyrelative to a cephalothorax of the Demodex mites.

In some configurations, discloses herein is a method of treatingblepharitis and/or rosacea, comprising topically applying formamidineparasiticides proximate one or more eyelashes, the topically applyingtherapeutically effective to preferentially be absorbed by a body of theDemodex mite with respect to ingestion by the Demodex mite sufficient tocause reduced movement of the body of the Demodex mite with respect to ahead of the Demodex mite, the method sufficient to reduce or eliminateDemodex mites proximate the eyelashes, resulting in improvement of themanifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a topical ophthalmicformulation for treating blepharitis in a patient, comprising aneffective amount of a formamidine parasiticide and a pharmaceuticallyacceptable vehicle, wherein the ophthalmic composition is sterile andnon-irritating to the eye, wherein the formamidine parasiticide is thesole active ingredient of the ophthalmic composition.

In some configurations, from about 0.01% to about 1% of the formamidineparasiticide with respect to the total weight of the composition isadministered.

In some configurations, about 0.03% by weight of the formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, about 0.10% by weight of the formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, the ophthalmic composition comprises an eyedrop, a cream, or an ointment.

In some configurations, the ophthalmic composition does not include anyessential oils.

In some configurations, the formamidine parasiticide is selected fromthe group consisting of: amitraz,N-(2,4-Dimethylphenyl)-N-methyformamidine (DPMF), and2,4-dimethylanaline.

In some configurations, disclosed herein is a method for the treatmentof symptoms of blepharitis and/or ocular rosacea in the eye(s), saidsymptoms being selected from the group consisting of a feeling ofburning of the eye, a feeling of smarting of the eye, a feeling ofdryness of the eye, an increased sensitivity to light, blurred vision,and a complication of ocular rosacea in the cornea, said methodcomprising topically administering directly to the conjunctiva and/or tothe cornea(s) of the eye(s) of an individual in need of such treatment,a thus effective amount of formamidine parasiticides, formulated into aneyewash composition with a pharmaceutically acceptable vehicle therefor,said eyewash composition being sterile, non-irritating and compatiblewith eye tissue.

In some configurations, from 0.001% to 10% by weight of formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically applyingformamidine parasiticides in a dosage sufficient to fill and eliminateDemodex mites on one or more anatomical locations, resulting incessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of formamidine parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied formamidine parasiticidesis formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of formamidine parasiticidesin said topically-applied lotion, cream, or gel is about one to fivepercent by weight.

In some configurations, said topically-applied formamidine parasiticidesis applied to eyelids.

In some configurations, said topically-applied formamidine parasiticidesis applied to affected skin areas at least once and not more than twicedaily for a period of about two to four weeks.

In some configurations, said topically-applied formamidine parasiticidesis encapsulated inside microliposomes before being formulated into saidcarrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation formamidine parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof cylindrical eyelash dandruff associated with blepharitis and/orocular rosacea in the eye(s), said method comprising topicallyadministering directly to the conjunctiva and/or to the cornea(s) of theeye(s) of an individual in need of such treatment, a thus effectiveamount of formamidine parasiticides, formulated into an eyewashcomposition with a pharmaceutically acceptable vehicle therefor, saideyewash composition being sterile, non-irritating and compatible witheye tissue.

In some configurations, from 0.001% to 10% by weight of formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically applyingformamidine parasiticides in a dosage sufficient to fill and eliminateDemodex mites on one or more anatomical locations, resulting incessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of formamidine parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied formamidine parasiticidesis formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of formamidine parasiticidesin said topically-applied lotion, cream, or gel is about one to fivepercent by weight,

In some configurations, said topically-applied formamidine parasiticidesis applied to eyelids.

In some configurations, said topically-applied formamidine parasiticidesis applied to affected skin areas at least once and not more than twicedaily for a period of about two to four weeks.

In some configurations, said topically-applied formamidine parasiticidesis encapsulated inside microliposomes before being formulated into saidcarrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation formamidine parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof symptoms of blepharitis and/or ocular rosacea in the eye(s), saidsymptoms being selected from the group consisting of a feeling ofburning of the eye, a feeling of smarting of the eye, a feeling ofdryness of the eye, an increased sensitivity to light, blurred vision,and a complication of ocular rosacea in the cornea, said methodcomprising topically administering directly to the conjunctiva and/or tothe cornea(s) of the eye(s) of an individual in need of such treatment,a thus effective amount of formamidine parasiticides, formulated into aneyewash composition with a pharmaceutically acceptable vehicle therefor,said eyewash composition being sterile, non-irritating and compatiblewith eye tissue.

In some configurations, from 0.001% to 10% by weight of formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically applyingformamidine parasiticides in a dosage sufficient to fill and eliminateDemodex mites on one or more anatomical locations, resulting incessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of formamidine parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied formamidine parasiticidesis formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of formamidine parasiticidesin said topically-applied lotion, cream, or gel is about one to fivepercent by weight.

In some configurations, said topically-applied formamidine parasiticidesis applied to eyelids.

In some configurations, said topically-applied formamidine parasiticidesis applied to affected skin areas at least once and not more than twicedaily for a period of about two to four weeks.

In some configurations, said topically-applied formamidine parasiticidesis encapsulated inside microliposomes before being formulated into saidcarrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation formamidine parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof cylindrical eyelash dandruff associated with blepharitis and/orocular rosacea in the eye(s), said method comprising topicallyadministering directly to the conjunctiva and/or to the cornea(s) of theeye(s) of an individual in need of such treatment, a thus effectiveamount of formamidine parasiticides, formulated into an eyewashcomposition with a pharmaceutically acceptable vehicle therefor, saideyewash composition being sterile, non-irritating and compatible witheye tissue.

In some configurations, from 0.001% to 10% by weight of formamidineparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of formamidine parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically applyingformamidine parasiticides in a dosage sufficient to fill and eliminateDemodex mites on one or more anatomical locations, resulting incessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of formamidine parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied formamidine parasiticidesis formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of formamidine parasiticidesin said topically-applied lotion, cream, or gel is about one to fivepercent by weight,

In some configurations, said topically-applied formamidine parasiticidesis applied to eyelids.

In some configurations, said topically-applied formamidine parasiticidesis applied to affected skin areas at least once and not more than twicedaily for a period of about two to four weeks.

In some configurations, said topically-applied formamidine parasiticidesis encapsulated inside microliposomes before being formulated into saidcarrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation formamidine parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof symptoms of blepharitis and/or ocular rosacea in the eye(s), saidsymptoms being selected from the group consisting of a feeling ofburning of the eye, a feeling of smarting of the eye, a feeling ofdryness of the eye, an increased sensitivity to light, blurred vision,and a complication of ocular rosacea in the cornea, said methodcomprising topically administering directly to the conjunctiva and/or tothe cornea(s) of the eye(s) of an individual in need of such treatment,a thus effective amount of phenylpyrazole parasiticides, formulated intoan eyewash composition with a pharmaceutically acceptable vehicletherefor, said eyewash composition being sterile, non-irritating andcompatible with eye tissue.

In some configurations, from 0.001% to 10% by weight of phenylpyrazoleparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically-applyingphenylpyrazole parasiticides in a dosage sufficient to fill andeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of phenylpyrazole parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied phenylpyrazoleparasiticides is formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of phenylpyrazoleparasiticides in said topically-applied lotion, cream, or gel is aboutone to five percent by weight.

In some configurations, said topically-applied phenylpyrazoleparasiticides is applied to eyelids.

In some configurations, said topically-applied phenylpyrazoleparasiticides is applied to affected skin areas at least once and notmore than twice daily for a period of about two to four weeks.

In some configurations, said topically-applied phenylpyrazoleparasiticides is encapsulated inside microliposomes before beingformulated into said carrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation phenylpyrazole parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof cylindrical eyelash dandruff associated with blepharitis and/orocular rosacea in the eye(s), said method comprising topicallyadministering directly to the conjunctiva and/or to the cornea(s) of theeye(s) of an individual in need of such treatment, a thus effectiveamount of phenylpyrazole parasiticides, formulated into an eyewashcomposition with a pharmaceutically acceptable vehicle therefor, saideyewash composition being sterile, non-irritating and compatible witheye tissue.

In some configurations, from 0.001% to 10% by weight of phenylpyrazoleparasiticides with respect to the total weight of the composition isadministered.

In some configurations, from 0.01% to 5% of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.03% by weight of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, 0.10% by weight of phenylpyrazole parasiticideswith respect to the total weight of the composition is administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically-applyingphenylpyrazole parasiticides in a dosage sufficient to fill andeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, said doses of phenylpyrazole parasiticides arerepeated about two to four times with spacing of three to seven daysbetween them.

In some configurations, said topically-applied phenylpyrazoleparasiticides is formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of phenylpyrazoleparasiticides in said topically-applied lotion, cream, or gel is aboutone to five percent by weight.

In some configurations, said topically-applied phenylpyrazoleparasiticides is applied to eyelids.

In some configurations, said topically-applied phenylpyrazoleparasiticides is applied to affected skin areas at least once and notmore than twice daily for a period of about two to four weeks.

In some configurations, said topically-applied phenylpyrazoleparasiticides is encapsulated inside microliposomes before beingformulated into said carrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation phenylpyrazole parasiticides in a dosage sufficient toeliminate Demodex mites on one or more anatomical locations, resultingin cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, disclosed herein is a method for the treatmentof symptoms of blepharitis and/or ocular rosacea in the eye(s), saidsymptoms being selected from the group consisting of a feeling ofburning of the eye, a feeling of smarting of the eye, a feeling ofdryness of the eye, an increased sensitivity to light, blurred vision,and a complication of ocular rosacea in the cornea, said methodcomprising topically administering directly to the conjunctiva and/or tothe cornea(s) of the eye(s) of an individual in need of such treatment,a thus effective amount of a drug used to treat Alzheimer's disease,formulated into an eyewash composition with a pharmaceuticallyacceptable vehicle therefor, said eyewash composition being sterile,non-irritating and compatible with eye tissue.

In some configurations, from 0.001% to 10% by weight of drug used totreat Alzheimer's disease with respect to the total weight of thecomposition is administered.

In some configurations, from 0.01% to 5% of drug used to treatAlzheimer's disease with respect to the total weight of the compositionis administered.

In some configurations, 0.03% by weight of drug used to treatAlzheimer's disease with respect to the total weight of the compositionis administered.

In some configurations, 0.10% by weight of drug used to treatAlzheimer's disease with respect to the total weight of the compositionis administered.

In some configurations, disclosed herein is a method of treatingblepharitis and/or rosacea by orally-administering or topically applyingdrug used to treat Alzheimer's disease in a dosage sufficient to filland eliminate Demodex mites on one or more anatomical locations,resulting in cessation of the manifestations of blepharitis and/orrosacea.

In some configurations, said doses of drug used to treat Alzheimer'sdisease are repeated about two to four times with spacing of three toseven days between them.

In some configurations, said topically-applied drug used to treatAlzheimer's disease is formulated in a carrier lotion, cream, or gel.

In some configurations, the concentration of drug used to treatAlzheimer's disease in said topically-applied lotion, cream, or gel isabout one to five percent by weight.

In some configurations, said topically-applied drug used to treatAlzheimer's disease is applied to eyelids.

In some configurations, said topically-applied drug used to treatAlzheimer's disease is applied to affected skin areas at least once andnot more than twice daily for a period of about two to four weeks.

In some configurations, said topically-applied drug used to treatAlzheimer's disease is encapsulated inside microliposomes before beingformulated into said carrier lotion, cream, or gel.

In some configurations, disclosed herein is a composition for treatingblepharitis and/or rosacea comprising an oral or topical pharmaceuticalformulation drug used to treat Alzheimer's disease in a dosagesufficient to eliminate Demodex mites on one or more anatomicallocations, resulting in cessation of the manifestations of blepharitisand/or rosacea.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-B schematically illustrate application of an ophthalmicformulation onto an eye with a Demodex infestation.

FIG. 2 illustrates data illustrating activity of selected anatomy ofDemodex mites following therapy with a topical formulation.

FIGS. 3A-3B show examples of formulations with amitraz and fluralaner.

FIGS. 4A-4C illustrate embodiments of various diagnostic techniques forDemodex that do not necessarily require epilation.

DETAILED DESCRIPTION

In some embodiments, disclosed herein are topical therapeutic agents,including but not limited to topical pharmaceutical agents including oneor more isoxazoline parasiticides, formamidine parasiticides, agentsused for treating Alzheimer's disease, and other agents as disclosedherein for the treatment of various ophthalmic and dermatologicconditions. Also disclosed herein are methods of treating blepharitis,ocular rosacea, and Demodex infestation in patients in need thereof. Insome embodiments, patients in need thereof can be treated with an activeagent from the isoxazoline parasiticide family of chemicals), whichinclude but are not limited to isoxazoline-substituted benzamidederivatives. Not to be limited by theory, isoxazoline parasiticides canact as GABA-chloride antagonists to selectively target the nervoussystem of certain organisms, including but not limited to Demodex. TheGABA-mediated chloride influx can lead to hyperpolarization of thecellular membrane and generates an inhibitory postsynaptic potential,which decreases the probability of an action potential, and lead toparalysis and eventual death of Demodex mites. The isoxazolineparasiticide can include, for example, any number of fluralaner,sarolaner, lotilaner, afoxolaner, and/or fluxametamide, includingderivatives, analogues, and L- and D-isomers thereof, including but notlimited to enantiomers, compositions comprising racemic mixtures, andenantiomerically pure compositions. In some embodiments, the isoxazolineparasiticide, formamidine parasiticide, or other active ingredients asdisclosed herein are the only active ingredient utilized in theformulation and/or method. In some embodiments, the isoxazolineparasiticide is an isoxazoline-substituted benzamide derivative. In someembodiments, the isoxazoline parasiticide has one, two, three, or morefluorine groups, such as trifluorine groups in its chemical structure(e.g., R—CF₃).

Isoxazoline parasiticides have been conventionally utilized forveterinary applications, including chews and non-ophthalmic topical“pour on” solutions, although to the inventors' knowledge no humanformulations have been developed. Non-limiting examples of isoxazolineparasiticides can be found, for example, in U.S. Pat. No. 7,662,972 toMita et al., U.S. Pat. No. 8,466,115 to Curtis et al., U.S. Pat. No.7,964,204 to Lahm et al., and U.S. Pat. No. 8,383,659 to Nanchen et al.,each of which are hereby incorporated by reference in their entireties.Additionally, U.S. Pub. No. 2010/0254960 A1, PCT Pub. No. WO 2007/070606A2, PCT Pub. No. WO 2007/123855 A2, PCT Pub. No. WO 2010/003923 A1, U.S.Pat. Nos. 7,951,828, 7,662,972, U.S. Pub. No. 2010/0137372 A1, U.S. Pub.No. 2010/0179194 A2, U.S. Pub. No. 2011/0086886 A2, U.S. Pub. No.2011/0059988 A1, US 2010/0179195 A1, PCT Pub. No. WO 2007/075459 A2 andU.S. Pat. No. 7,951,828, all of which are incorporated by reference intheir entireties, describe various other parasiticidal isoxazolinecompounds. Veterinary oral formulations such as chews result in firstpass liver metabolism as well as systemic effects, which can beundesirable in some cases for targeted local applications. A significantchallenge is that the fluorinated and/or chlorinated groups of certainisoxazoline parasiticides cause these molecules to be highly insolublein any pharmaceutical-based solutions including oil and water-basedsolutions, and having a solubility of less than about 1 mg/kg, or 1mg/mL aqueous concentrations, or even less. Veterinary topical solutionsof isoxazoline parasiticides have included, for example,dimethylacetamide, glycofurol, diethyltoluamide, and/or acetone.However, such solutions are only indicated as a “pour on” solution onthe back of the neck of an animal, such as a cat or a dog, areunsuitable for ophthalmic use (and potentially toxic) and includeinstructions not to administer the solution in or around the eye. Such“pour on” solutions are absorbed systemically by the animal and do notresult in targeted local activity only. To the inventors' knowledge, noisoxazoline parasiticides or formamidine parasiticide topical ophthalmicformulations have previously been developed. Therapeutic formulationsthat are safe and non-toxic for ocular use, and sufficiently soluble tobe therapeutically efficacious to treat ocular Demodex and relatedconditions such as blepharitis, for example, are needed.

It has now been determined that compounds of the family of theisoxazoline parasiticides, formamidine parasiticides, agents to treatAlzheimer's disease, and/or other agents as disclosed elsewhere hereincan be suitable for the treatment of ophthalmic pathologies of anyorigin, particularly ophthalmic pathologies due to Demodex folliculorum,and more particularly blepharitis and/or ocular rosacea. Otherconditions that can be treated via formulations and methods as disclosedherein include, for example, rosacea, Pityriasis folliculorum,rosacea-like demodicosis, and demodicosis gravis, nonspecific facialdermatitis, steroid rosacea, androgenetic alopecia, madarosis, lupusmiliaris disseminates faciei, dissecting folliculitis, perioraldermatitis, acarica blepharo-conjuncitivitis, papulopustular scalperuptions, eosinophilic folliculitis, pustular folliculitis, Grover'sdisease, and Demodex abscess.

Ivermectin is another drug that has been used to treat Demodex, and isgenerally more soluble than the isoxazoline parasiticides in solution.However, no known formulations are approved for ocular use (e.g., forblepharitis), and more efficacious therapeutic agents are needed. Insome embodiments, a formulation and/or method does not involve anavermectin such as ivermectin or another macrocyclic lactone derivative.However, formulations can include an avermectin in other embodiments.

Disclosed herein are various embodiments of systems, methods, andformulations for the treatment of various eye conditions including butnot limited to blepharitis, and the treatment of Demodex infestations(e.g., on the eyelid of a subject, such as a human). Embodiments caninclude any number of features as disclosed herein. Some embodiments donot include dimethylacetamide, glycofurol, diethyltoluamide, and/oracetone, at least some of which can be toxic or irritating to the eye insome cases.

Also disclosed herein is the use of topical isoxazoline parasiticides,formamidine parasiticides, agents to treat Alzheimer's disease, and/orother agents as disclosed elsewhere herein for the treatment ofblepharitis and methods of treating Demodex infestation and blepharitisin patients in need thereof.

Further disclosed are topical isoxazoline parasiticides, formamidineparasiticides, agents to treat Alzheimer's disease, and/or other agentsas disclosed elsewhere herein for the treatment of rosacea and/or ocularrosacea and methods of treating Demodex infestation and rosacea and/orocular rosacea in patients in need thereof (e.g., from the isoxazolineparasiticides family of chemicals). Formulations and methods of reducingDemodex mite count proximate the eye of the patient and cylindricaleyelash dandruff are also disclosed.

Also disclosed herein is topical isoxazoline parasiticides, formamidineparasiticides, agents to treat Alzheimer's disease, and/or other agentsas disclosed elsewhere herein for the treatment of rosacea and/or ocularrosacea and methods of treating Demodex infestation and rosacea and/orocular rosacea in patients in need thereof.

According to some embodiments, the pharmaceutical composition caninclude at least one, two, or more compounds selected from the family ofthe isoxazoline parasiticides including, for example, fluralaner,sarolaner, lotilaner, afoxolaner, and/or fluxametamide, is administeredin particular for the treatment of conjunctivitis, blepharitis, ocularrosacea, or other indications including other ocular surface diseasessuch as meibomian gland dysfunction or dry eye disease.

Some embodiments can include derivatives, analogues, and L- andD-isomers of isoxazoline parasiticides, formamidine parasiticides, orother active therapeutic agents as disclosed elsewhere herein, includingbut not limited to enantiomers, compositions comprising racemicmixtures, and enantiomerically pure compositions.

In some embodiments, a dose of isoxazoline parasiticides, formamidineparasiticides, agents to treat Alzheimer's disease, and/or other agentsas disclosed elsewhere herein can surprisingly be used that is lowerthan what has been shown to be clinically effective in veterinarymedicine, which acts via systemic absorption via topical rinses orwashes (e.g., at concentrations in the 1-10 nM, or 100 pM-1 nM range),or ranges including any two of the foregoing values. These lowereffective concentrations may be, without limitation, due to directabsorption of drug by the mite body rather than ingestion of drug by themite, with the abdomen of the mites being thinner (˜0.5 um) and morelikely to absorb drug than the mites' cephalothorax (˜2 um). In someembodiments, direct absorption of drug by the mite body can be themechanism responsible for at least about 50%, 60%, 70%, 80%, 90%, ormore of the total uptake of the drug by the mite.

In some embodiments, daily and local treatment is administered ratherthan a large long-acting systemic dose (as has been done in veterinarymedicine once a month, every 8 weeks, every 12 weeks, every 16 weeks, orless frequently). However, long-acting systemic or local doses could beused in other embodiments.

In some embodiments, dosing could be, for example, about or at leastabout 1, 2, 3, 4, 5, 6, 7, 8, or more times daily, such as 1 to 2 timesdaily. In some embodiments, therapy could also be weekly, single dose ora limited-course of treatment. In some embodiments, a formulation can bepreferentially used in the morning, at night, or only at night, totarget exposure of mites during mating hours.

In some embodiments, formulations can be advantageous in part due to theslow elimination rate of molecules such as isoxazoline parasiticides,however, a small and local dose allows the repeated and frequent dosing,which may be advantageous to disrupt the Demodex life cycle througheffects on more susceptible juvenile forms, without associated systemicrisks and side-effects.

In some embodiments, an active molecule may preferentially behydrophobic, so it concentrates in regions with either sebum or meibumoils (e.g., eye lash follicles and/or meibomian glands). A formulationmay be preferentially water-based to facilitate delivery to andabsorption by the hydrophilic chitinous chitosan exterior of Demodexmites.

In some embodiments, a therapeutic agent can be delivered in the form ofa drop, cream, ointment, eye wash, wipe, salve, or gel, or immediate orsustained release formulation. In some embodiments, a therapeutic agentcan be delivered in the form of a punctal or canalicular plug oremulsion. In some cases, a form of an oily, gel-like, viscous ointmentmay also impede Demodex mite movement across the skin surface duringmating.

In some embodiments, an isoxazoline parasiticide, formamidineparasiticide, agents to treat Alzheimer's disease, and/or other agentsas disclosed elsewhere herein formulation may have preferentialselectivity for the receptors of insects/mites/acari oververtebrate/mammalian/human receptors.

In some embodiments, an active agent is delivered in an oral formulation(e.g., tablet, capsule, solution, etc.), and a very small dose may bedelivered to avoid meaningful systemic exposure or non-local dermalexposure (in contrast to veterinary teachings). However, in someembodiments, an active agent is delivered in a non-oral formulation,such as a topical formulation, e.g., a topical ophthalmic formulation.

In some embodiments, a dose of between, for example, 1 microgram to 1mg/ml or 0.0001%-1% active agent (e.g., isoxazoline parasiticides,formamidine parasiticides, agents to treat Alzheimer's disease, and/orother agents as disclosed elsewhere herein) by weight, or between about0.01% and 10% by weight, between about 0.05% and about 0.5% by weight,or about 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%,0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%,0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%,0.95%, 1.00%, or ranges including any two of the aforementioned values,or 1 ng-1 microgram/ml or 0.0000001-0.0001% active agent (e.g.,isoxazoline parasiticides, formamidine parasiticides, agents to treatAlzheimer's disease, and/or other agents as disclosed elsewhere herein)by weight, or 1 mg/ml-100 mg/ml or 0.1-10% active agent (e.g.,isoxazoline parasiticides, formamidine parasiticides, agents to treatAlzheimer's disease, and/or other agents as disclosed elsewhere herein)by weight, or ranges including any of the foregoing values. In someembodiments, the isoxazoline parasiticides, formamidine parasiticides,agents to treat Alzheimer's disease, or other agents as disclosedelsewhere herein are the only active agent.

In some embodiments, an ophthalmic formulation can be configured fordelivery directly onto an ocular surface, including but not limited tothe conjunctiva and/or cornea of the eye. In some embodiments, anophthalmic formulation can be configured for delivery directly orindirectly onto any number of the anterior or posterior eyelids, eyelashes, or eyebrows. In some embodiments, an ophthalmic formulation isnot directly delivered to any number of the conjunctiva, cornea,anterior or posterior eyelids, eye lashes, or eyebrows.

An eyedrop formulation may be designed to specifically andsimultaneously treat blepharitis and Demodex in both the eyelashfollicles and/or the meibomian glands, without limitation due to oilyadditives, emulsions, ointment or cream based formulations, deliveryinstrument such as lash brushes, or site of application. In someembodiments, a “Drop and Coat the Lashes” (DACTL) technique can be used.A patient can be instructed to close the eye(s) upon administration,thus causing the formulation to come into contact with the orifices ofthe meibomian glands on the margin(s) of the eyelid, and for theformulation to accumulate outside of the lid margin. The patient canthen utilize their finger or an applicator to spread formulation whichhas accumulated outside of the lid margin onto the eye lashes and/orfollicles of the eye lashes on the lower and/or upper eye lashes. Not tobe limited by theory, as Demodex mites reside in both the eye lash hairfollicles and in the meibomian glands, it can be advantageous for theeye drop formulation to be directly applied to one or both of theselocations. Since these two targets in combination are unique to thisdisease, a therapeutic agent can be delivered to these locationssimultaneously. The meibomian gland orifices are on the superior andinferior surfaces of the lower and upper eyelids, respectively. An eyedrop placed directly onto the ocular surface thus allows for delivery offormulation directly to the upper and lower meibomian gland orifices.

Methods of treating blepharitis and/or Demodex infestation can include aformulation/treatment (or similar) delivered specifically by applying adrop in the eye, and then using a finger or instrument (e.g., lashbrush) to coat the base of hair follicles in the upper and/or lowereyelids. In some embodiments, desirable features of a formulation caninclude any number of maximizing drug aqueous solubility to enhancebioavailability (in solution and suspensions), improve the residencetime of the drug product in the eye using polymers/viscosity agents, andachieve acceptable visual acuity and comfort.

The viscosity of the formulation may be sufficiently high in someembodiments to cause coverage of formulation over meibomian glandorifices on upper and/or lower lid margins upon blinking or close of theeye.

In some cases, viscosity may be sufficiently high to slow evacuation offormulation through the puncta of the eye for at least 5 seconds, or 10seconds or 20 seconds or 30 seconds or longer, to enhance contact timeof formulation with meibomian gland orifices and to cause theformulation to spill over the lid margin to where it can be accessed fordelivery to the eyelash follicles (e.g., by runoff, and/or by spreadingof formulation using a finger and/or instrument).

Formulation constituents can be chosen to enable dissolution of activeagent into a solution, but with a low concentration by weight of organicsolvents, e.g., ≤50%, 20%, 10%, 5%, 2%, or 1%, or less or more by weightorganic. This may be achieved at least in part by using a surfactantsuch as, for example, polysorbate-80 or polysorbate-20. In some cases,low concentrations of polysorbate 80 may be preferentially used, sincehigher concentrations may lead to isoxazoline parasiticides hydrolysis(e.g., 0.001-0.1% polysorbate 80 by weight).

In some cases, this can also be achieved and solubility of isoxazolineparasiticides enhanced through organic solvents such as propyleneglycol.

Solubility and viscosity may be also simultaneously enhanced byselection of an appropriate additive, thereby minimizing osmolarity,e.g., with polyvinyl alcohol, carboxymethylcellulose or the like.

Formulation constituents can be chosen to enable dissolution of activeagent (e.g., isoxazoline parasiticides or other active agents) into asolution, and one that is stable from hydrolytic reactions for up to 1,1.5, 2 years, or more to enable commercial shelf life e.g., with anoptimal pH range of neutral to slightly alkaline (e.g., pH 7-10, 7-7.5,or pH 5-7 in other embodiments).

The buffer concentration required to achieve the desired pH can beminimized in some cases, and thus retarding the hydrolysis rate (e.g.,phosphate buffer concentration 0.01-0.1M). This may also be achievedwith organic solvents and surfactants at concentration ranges describedabove.

Cationic surfactants, through creation of cationic micelles, can also beadvantageous by retarding the hydrolysis rate.

Emulsions and emulsifiers may be mixed with water to shield isoxazolineparasiticides, formamidine parasiticides, agents to treat Alzheimer'sdisease, and/or other agents and/or other active agents from water in anoil-in-water droplet, e.g., with a carbodiimide additive to prolongstability by forming more complex water-free micelles.

Water scavengers such as Stabaxol I®(bis-2,6-diisopropylphenylcarbodiimide) may be added to achievelong-term oil-based formulations to clean solvents of water.

The pharmaceutical compositions in some embodiments can comprise atleast one compound selected from among the family of the isoxazolineparasiticides, formamidine parasiticides, agents to treat Alzheimer'sdisease, and/or other agents and/or other active agents, areparticularly useful for the treatment of ophthalmic symptoms, symptomsselected from a feeling or sensation of burning or of smarting of theeye, a feeling or sensation of a foreign body in the eye, a feeling orsensation of dryness of the eye, an increased sensitivity to light,blurred vision, telangiectasia of the eyelid margin, meibomitis,chalazia, conjunctival hyperemia and papillary conjunctivitis.

The term “treatment” can include treatment in humans and/or otheranimals.

The pharmaceutical compositions according to some embodiments of theinvention can be useful for the treatment of the eyes topically, orally,parenterally or rectally.

The topical application is the most common method of administration ofophthalmic medicaments. The topical route makes possible theinstillation into the eye of drops or the application in the eye ofsolutions, eyewashes, suspensions, salves, ointments, gels, sprays,foams, powders, lotions, viscoelastic solutions and/or the deploying ofsolid forms at the surface of the eye, impregnated pads, syndets orwipes.

Some formulations can also be provided in the form of suspensions ofmicrospheres or nanospheres or of vesicles formed from lipid or polymeror of polymeric patches and of hydrogels making possible controlledrelease. These compositions for topical application can be provided inanhydrous form, in aqueous form or in the form of an emulsion.

The pharmaceutical compositions for topical application are preferablynon-irritating and compatible with the tissues of the eye. The solutionscan be sterile preparations and can be free from all particles. Thesuspensions can be sterile preparations, and can include solid particlesin a liquid vehicle appropriate for ocular instillation. The ointmentscan be semisolid and sterile preparations.

Orally, the pharmaceutical compositions can be provided in liquid, pastyor solid form, in the form of powders and more particularly in the formof tablets, including sugar-coated tablets, hard gelatin capsules,syrups, suspensions, solutions, powders, granules, emulsions,microspheres or nanospheres or vesicles formed from lipid or polymermaking possible controlled release. Parenterally, the compositions canbe provided in the form of solutions or suspensions for infusion or forinjection. Rectally, the compositions can be provided in the form ofsuppositories. In some cases, the pharmaceutical compositions aretopical ophthalmic compositions, and not oral or rectal compositions.

The compositions can in some embodiments comprise from 0.001% to 10% ofat least one compound selected from the family of isoxazolineparasiticides, formamidine parasiticides, agents to treat Alzheimer'sdisease, and/or other agents as disclosed herein, by weight with respectto the total weight of the composition. In some embodiments, thecompositions according to the invention comprise from 0.01% to 5% of atleast one compound selected from the family of the isoxazolineparasiticides, by weight with respect to the total weight of thecomposition.

In some embodiments, the compositions according to the invention areprovided in the form of an eyewash or of eye drops. The term “eyewash”means a liquid formulation specifically appropriate for administrationto the conjunctiva of the eye and the cornea. The eyewash can include avolume of the instilled drops of, e.g., approximately 25-50 microliters.In some embodiments, compositions are supplied as a kit, for example aneyedrop and shampoo, and may be used along with sterilizing agents suchas tea tree oil and derivatives, and hypochlorous acid, which have alsobeen shown to have Demodex activity, or not include tea tree or otheroils in some cases.

As indicated above, the compositions can in some embodiments meetspecific conditions in order to be applied in the eye. Such conditionsinclude, in particular, sterility, absence of irritation andcompatibility with the tissues of the eye. The latter criterion is moredifficult to obtain than for a composition applied to the skin; inparticular, compounds such as ethanol or glycols, formulated incompositions to be applied to the skin, cannot in some cases be includedin compositions for ocular use.

The topical compositions can make it possible to directly andspecifically treat the symptoms of the pathology in the eye and eyelidsby a local action; in particular, since only the eye is targeted, abetter effectiveness can be expected.

In some embodiments, a formulation can be in a solution, suspension,cream, ointment, or other form.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort may be maximized as much as possible, although sometimesformulation considerations (e.g., drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid may be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid may either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water. Ophthalmic solutions maypreferably be maintained at a comfortable pH with an appropriate buffersystem. The formulations may also contain pharmaceutically acceptablepreservatives, stabilizers and surfactants.

In some embodiments, a topical formulation does not include a dermalpenetration enhancer, which could increase systemic absorption and becontrary to the intent of maintaining the formulation locally at orproximate the site of application in some cases. In some embodiments, aformulation does not include any dermal penetration enhancers, such asone or more of Laurocapram (Azone®) and laurocapram derivatives, such as1-alkylazacycloheptan-2-ones, and oleic acid and its ester derivatives,such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate, and sorbitan esters such as sorbitan monolaurate andsorbitan monooleate, and other fatty acid esters such as isopropyllaurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate,propylene glycol monolaurate and propylene glycol monooleate, and longchain alkyl esters of 2-pyrrolidone, particularly the 1-lauryl, 1-hexyland 1-(2-ethylhexyl) esters of 2-pyrollidene and those dermalpenetration enhancers such as dodecyl (N,N-dimethylamino) acetate anddodecyl (N,N-dimethylamino) propionate and 2-n-nonyl-1-3-dioxolane.However, some embodiments of formulations can include one or more dermalpenetration enhancers.

In some embodiments, a topical formulation can include one or moregelling agents. The gelling agent could be a copolymer, such as Pemulen™TR1 and/or TR2 polymeric emulsifiers (Lubrizol Corp., Wickliffe, OH)which are high molecular weight, copolymers of acrylic acid and C10-C30alkyl acrylate crosslinked with allyl pentaerythritol. They are fluffy,white powders and are primarily used to form stable oil-in-wateremulsions. Pemulen polymers include both hydrophilic and hydrophobicportions within the molecule. The hydrophobic portion of the polymeradsorbs at the oil-water interface, and the hydrophilic portion swellsin the water forming a gel network around the oil droplets to provideemulsion stability. Pemulen polymers can form stable oil-in-wateremulsions without the need for any additional surfactants. Therefore,they can be advantageous for developing low irritancy lotions andcreams, for example. Pemulen polymers provide viscosity building andhigh yield value to allow for suspension and stabilization of insolublematerials and particulates. In some embodiments, the gelling agent canbe absent, or present in the formulation between about 0.001% and about1%, between about 0.01% and about 0.10%, or about 0.001%, 0.005%, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%,0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50% w/w of the formulation,or ranges including any two of the foregoing values.

In some embodiments, an oil-based formulation such as a cream, ointment,or emulsion for example can include one or more of mineral oil, castoroil, or petrolatum, such as between about 20% and about 80%, or betweenabout 30% and about 70% w/w of the formulation. The formulation can alsoinclude a cyclodextrin as a carrier molecule to facilitate dissolution.

In some embodiments, a topical formulation can include one or morethickening agents, including a polysaccharide thickener, such ashydroxypropylmethylcellulose (HPMC) and sodium CMC. In some embodiments,the thickening agent can be present between about 0% and about 2%,between about 0.10% and about 1.00%, between about 0.25% and about1.00%, or about 0.10%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.50%, 0.60%,0.70%, 0.80%, 0.90%, 1.00% w/w of the formulation, or ranges includingany two of the foregoing values, such as between about 0.1% and about0.5%. In some embodiments, the formulation can have a viscosity ofbetween about 50 cP and about 100 cP in order to increase the residencetime of the formulation in the eye. In some embodiments, a formulationcan include a viscosity, for example, of at or above 5 cP or 20 cP or 40cP or 100 cP or 250 cP or 400 cP or 1000 cP or more, or ranges includingany two of the foregoing values. In some cases, the formulation isconfigured to have a residence time in the eye of between about 90seconds and about 10 minutes, or about or at least about 60 seconds, 90seconds, 120 seconds, 180 seconds, 240 seconds, 300 seconds, 6 minutes,7 minutes, 8 minutes, 9 minutes, 10 minutes, or ranges including any twoof the foregoing values.

In some embodiments, a topical formulation can include one or moresolubilizer agents and/or surfactants, including a non-ionic surfactantsuch as a polysorbate, such as Polysorbate 80, Polysorbate 65,Polysorbate 60, Polysorbate 40, or Polysorbate 20. In some embodiments,Polysorbate 80 has been found to unexpectedly result in increasedsolubility of an isoxazoline parasiticide over other polysorbates. Othersurfactants, such as a fluorinated surfactant for example can besubstituted or used in addition to a non-ionic surfactant. In someembodiments, the solubilizer agents and/or surfactants can be presentbetween about 0% and about 5%, between about 0.10% and about 4%, betweenabout 0.50% and about 4%, or about 0.50%, 0.75%, 1.00%, 1.25%, 1.50%,1.75%, 2.00%, 2.25%, 2.50%, 2.75%, 3.00%, 3.25%, 3.50%, 3.75%, 4.00%,4.25%, 4.50%, 4.75%, 5.00% w/w of the formulation, or ranges includingany two of the foregoing values. Polysorbate-80 may also be replacedwith Cremphor EL (hydrogenated castor oil) up to FDA monograph limits of5%, such as about 1%, 2%, 3%, 4%, or 5%, or between about 1% and 5%, orranges including any two of the aforementioned values, to facilitatehigher drug concentrations.

In some embodiments, a formulation (including but not limited to an eyedrop, cream, ointment, or other form as disclosed elsewhere herein) caninclude both a castor oil (e.g., hydrogenated castor oil) and apolysaccharide thickener such as HPMC or sodium CMC. In some cases, thecombination can advantageously and unexpectedly form a long-lasting filmlayer.

In some embodiments, a topical formulation can include one or moretonicity agents, such as glycerin, dextrose, mannitol, potassiumchloride, and/or sodium chloride, for example. In some embodiments, thetonicity agent(s) can be present between about 0% and about 5%, betweenabout 0.10% and about 4%, between about 0.50% and about 4%, or about0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%, 2.75%,3.00%, 3.25%, 3.50%, 3.75%, 4.00%, 4.25%, 4.50%, 4.75%, 5.00% w/w of theformulation, or ranges including any two of the foregoing values.

In some embodiments, a topical formulation can include one, two, or morebuffering agents. Buffering agents can include, for example, acetatebuffers, citrate buffers, phosphate buffers and borate buffers. Acids orbases may be used to adjust the pH of these formulations as needed. Thebuffering agent could be one or more of sodium bicarbonate buffer,calcium bicarbonate buffer, tris(hydroxymethyl)aminomethane (Tris orTHAM), MOPS (3-(N-morpholino)propanesulfonic acid) buffer, HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA(N-(2-acetamido)-2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid),buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer,MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolaminebuffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphatebuffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer,PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid) buffer; TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanolbuffer, as well as combinations thereof. In some embodiments, thebuffering agent is Tris and/or disodium hydrogen phosphate (Na₂HPO₄) andsodium dihydrogen phosphate heptahydrate (NaH₂PO₄7H₂O). In someembodiments, the buffering agents can be present between about 0% andabout 2%, between about 0.01% and about 1%, between about 0.01% andabout 0.75%, or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.20%, 0.25%,0.30%, 0.35%, 0.40%, 0.45%. 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%,0.80%, 0.85%, 0.90%, 0.95%, 1.00% w/w of the formulation, or rangesincluding any two of the foregoing values. The buffering agents can beselected in a therapeutically effective amount such that the pH of thepharmaceutical composition can be, for example, between about 7.35 andabout 7.65, between about 7.45 and 7.55, or about 7.30, 7.35, 7.40,7.45, 7.50, 7.55, 7.60, or ranges including any two of the foregoingvalues.

In some embodiments, a topical formulation can include one or morepreservative agents, including but not limited to lauralkonium chlorideand benzalkonium chloride. Other preservatives can include, for example,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. In some embodiments, the preservative agent canbe present in the topical formulation between about 0.001% and about0.1%, between about 0.001% and about 0.01%, or about 0.001%, 0.002%,0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010% w/w ofthe formulation, or ranges including any two of the foregoing values.

The pharmaceutical compositions according to some embodiments of theinvention can additionally comprise inert additives or combinations ofthese additives, such as: wetting agents, emollients; agents forimproving flavor; preservatives; stabilizing agents; agents forregulating moisture; pH-regulating agents; buffers; agents for modifyingosmotic pressure; emulsifying agents; agents for increasing viscosity;and antioxidants. Ophthalmically acceptable antioxidants include, butare not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium (EDTA), although other chelating agents may also be used inplace or in conjunction with it.

In some embodiments, a pharmaceutical composition can include atocopherol. In some cases, a tocopherol can be effective in preventingdegradation of an isoxazoline in water. In some cases, the vitamin E isa tocopherol; in a further embodiment the tocopherol is an alpha- or agamma-tocopherol; more preferred is an alpha-tocopherol. In someembodiments, a pharmaceutical composition does not include a tocopherol.

In some embodiments, a pharmaceutical formulation does not include anyessential oils, such as tea tree oil, alpha-Terpineol, Cardinene,d-Carvone, 1-Carvone, gamma-Terpinene, alpha-Terpinene, 1,8-Cineole,alpha-Terpineol, para-Cimene, alpha-Pinene, Limonene, alpha-Thugene,Eucalyptol, (+)-Ledene, Cuminic Aldehyde, or Myrcene. However, someembodiments can include one or more of the foregoing essential oils.

In some embodiments, optional compound or compounds can be added tothese compositions such that the advantageous properties intrinsicallyassociated with some embodiments of the present invention are not, ornot substantially, detrimentally affected by the envisaged addition, forexample tetracyclines or omega-3 fatty acids, which may have favorableeffects in blepharitis.

In some embodiments, an isoxazoline parasiticide is administered orallyto a patient with blepharitis, rosacea, or other conditions as disclosedelsewhere herein. Because one target organism, Demodex folliculorum(and/or Demodex brevis), is an ectoparasite in the mite family, aneffective treatment in some cases is therapeutically eradicating theentire life cycle of such a microscopic insect, including egg, larval,and adult stages. For this reason, some embodiments treat blepharitisand/or rosacea patients with at least two doses timed so that betweenabout three and about seven days separate the doses. Such spacing allowstime for Demodex eggs to hatch into immature mites that are killedbefore they can mature into egg-producing adults. In some embodiments,1, 2, 3, 4, or more doses at three- to seven-day intervals could beemployed. After an isoxazoline parasiticide or other active agent asdisclosed herein carries out its miticidal activity on skin Demodexfolliculorum organisms (and/or Demodex brevis organisms), inflammatoryresponses to them begin to diminish but remnants of the dead mites stillelicit some flushing and lesion formation until the cleanup processes ofthe body remove them, a process requiring six to eight weeks in somecases. During this initial phase of administration, other medicationssuch as oral tetracycline and topical metronidazole, and/oranti-inflammatory agents such as NSAIDs and/or steroids can be employedto suppress early flareups and to give early clinical response. However,in some embodiments, a formulation or method does not involve atetracycline or other antibiotic, steroid, and/or metronidazole. Afterprolonged intervals of freedom from symptoms, should classic signs beginto reappear, treatment can be repeated.

In an alternative embodiment, isoxazoline parasiticides can beformulated into a cosmetically acceptable topical lotion, cream, or geland applied to skin, eyelids, eyelashes, meibomian glands, or otheranatomical locations as noted elsewhere herein. In some cases, such aroute of treatment can require once- or twice-daily applications for aslong as four weeks to achieve sufficient follicle penetration andeffective miticidal activity. A topical formulation that could achievethis effect could contain, for example, about 0.01-5% active ingredientin some cases and could be enhanced in penetration if the active agentwere encapsulated inside microliposomes. Such a topical treatment wouldlikely need to be repeated more frequently than the preferred oralembodiment, but a disease-free interval should be achieved by eachcourse of therapy.

In some embodiments, the pharmaceutical formulation including anydisclosed herein can be configured to advantageously allow foreradication of the mite proximate an eyelash via preferential absorptionof the pharmaceutical formulation through the exoskeleton (e.g., abdomenor opisthosoma) of the mite rather than ingestion of the pharmaceuticalformulation by the mite (e.g., by ingesting skin cells, sebum, and otherelements that could include an amount of active agent via systemicabsorption). Not to be limited by theory, Demodex mites have ahydrophobic chitin outer surface, and a relatively thin exoskeleton inthe abdomen/opisthosoma area (about 0.5 μm, vs. about 2.0 μm for thecephalothorax portion), which surprisingly has allowed for more rapidabsorption of the formulation through the abdomen, instead of primarilyvia ingestion as in previous veterinary formulations of isoxazolineparasiticides. FIGS. 1A-B schematically illustrate application of aformulation 120 onto an eye 140 with an iris/pupil 142. An eyelid aroundthe eye 140 may include a hair follicle 180 for an eyelash 186 and thefollicle 180 may include sebum oil 182. The eyelid may include ameibomian gland 160 with meibum oil 162. As shown in FIGS. 1A-B, a “facedown” orientation of the mites (e.g., Demodex folliculorum 164, Demodexbrevis 184) with respect to the hair follicle 180 or a Meibomian gland160 (with the mite body pointing to the opening of the follicle 180 orthe gland 160) may facilitate the preferential abdominal absorption ofthe formulation 120 through abdomen/opisthosoma area 190. In ex vivostudies, it has been surprisingly observed that following delivery ofcertain pharmaceutical formulations as disclosed herein that the abdomenand tail portion of a Demodex mite stops moving more quickly than thecephalothorax as in FIG. 2 , indicating Demodex mites are especiallysusceptible to topical ophthalmic formulations as disclosed herein.

In some embodiments, compositions and methods as disclosed herein can beused alone or in combination with any number of the following agents, intopical or other forms, which can be made into formulations havingparameters including any features including but not limited toconcentrations, excipients, and other features or absence of otherfeatures as disclosed elsewhere herein: albendazole, cambendazole,fenbendazole, flubendazole, mebendazole, oxfendazole, parbendazole,thiabendazole, triclabendazole, amitraz, demiditraz, clorsulon,closantel, oxyclozanide, rafoxanide, cyphenothrin, flumethrin,permethrin, promazine, derquantel, diamphenethide, dicyclanil,dinotefuran, imidacloprid, nitenpyram, thiamethoxam, abamectin,doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin,milbemycin oxime, emodepside, epsiprantel, fipronil, fluazuron,fluhexafon, indoxacarb, levamisole, lufenuron, metaflumizone,methoprene, monepantel, morantel, niclosamide, nitroscanate, nitroxynil,novaluron, oxantel, praziquantel, pyrantel, pyriprole, pvriproxyfen,sisapronil, spinosad, spinetoram, lindane, picrotoxin, dieldrin,alpha-endosulfan, and/or triflumezopyrim. In some embodiments,compositions and methods can include a meta-diamide (e.g.,broflanilide), a cyclodiene, and/or a macrocyclic lactone (includingavermectins and milbemycin). In some embodiments, an Alzheimer's diseasedrug can be the active agent, such as galantamine, donepezil and otherpiperidine analogues, rivastigmine and other carbamate analogues,tacrine, 7-methoxytacrine, other pyridine analogues, huperzine A andother alkaloid analogues, which can also have anti-Demodex activity.Galantamine for example is a selective, competitive rapidly reversibleacetylcholinesterase inhibitor with the anionic substrate and aromaticgorge, and an allosteric ligand/activator at the nicotinic cholinergicreceptors, thus increasing GABA activity. Other acetylcholinesteraseinhibitors could be utilized as well in some cases. Derivatives,analogues, and L- and D-isomers thereof, including but not limited toenantiomers, compositions comprising racemic mixtures, andenantiomerically pure compositions of any of the foregoing in thisparagraph can also be utilized. In some embodiments, a formulation doesnot include any number of, or all of the agents listed in thisparagraph.

In some embodiments, a dermatologic and/or ophthalmologic formulationcan include an active therapeutic agent of a formamidine parasiticideinstead of, or in addition to an isoxazoline parasiticide as disclosedabove. A formamidine parasiticide can be, for example, amitraz, whichcan function as an octopamine receptor modulator.N-(2,4-Dimethylphenyl)-N-methyformamidine (DPMF), a metabolite ofamitraz, is thought to be an active agent that exerts acaricidal andinsecticidal effects by acting as an agonist on octopamine receptors,and can be another active therapeutic agent, alone or in addition.2,4-dimethylanaline is a hydrolysis metabolite of DPMF and can also bean active therapeutic agent in other embodiments. Derivatives,analogues, and L- and D-isomers thereof, including but not limited toenantiomers, compositions comprising racemic mixtures, andenantiomerically pure compositions can also be utilized. In someembodiments, a dermatologic and/or ophthalmologic formulation caninclude an active therapeutic agent of a phenylpyrazole parasiticideinstead of, or in addition to an isoxazoline or formamidine parasiticideas disclosed above. The chemical structures of these insecticides arecharacterized by a central pyrazole ring with a phenyl group attached toone of the nitrogen atoms of the pyrazole. Some non-limiting examples ofphenyl pyrazole parasiticides include, for example, acetoprole,ethiprole, fipronil, flufiprole, pyraclofos, pyrafluprole, pyriprole,pyrolan, and vaniliprole.

To further illustrate some embodiments and advantages thereof, Table 1below lists several non-limiting specific examples of topicalisoxazoline parasiticide formulations for illustrative purposes only.All ingredients are listed as % w/w or grams/100 grams of preparation,and FIGS. 3A-3B shows examples of formulations with amitraz andfluralaner.

One example embodiment of an amitraz solution includes 0.100% w/w ofAmitraz in 99.9% light mineral oil. Another example of an amitrazointment can include 0.100% w/w of Amitraz and 29.9% mineral oil and70.0% petrolatum.

TABLE 1 Ingredient Solution 1 Solution 2 Suspension 1 Fluralaner 0.01000.0250 0.500 Pemulen TR1 0 0 0.050 HPMC 0.50 0.50 0 Polysorbate 80 2.02.0 2.0 Glycerin 2.5 2.5 2.5 TRIS 0 0 0.050 NaH₂PO₄7H₂O 0.44 0.44 0Na₂HPO₄ 0.045 0.045 0 pH 7.5 7.5 7.5 Lauralkonium Chloride 0.0050 0.00500.0050 Water q.s. ad 100% q.s. ad 100% q.s. ad 100%

In some embodiments, a topical ophthalmic formulation can include thefollowing instructions for use. A patient can be instructed to shower orbathe first before applying the study medication and to wash their handsbefore applying the study medication. A unit dose, such as a single dropof the formulation can be directly applied into each eye once or twice aday, e.g., once in the morning and once in the evening. After deliveringthe drop to the conjunctiva and/or cornea of the eye, the patient canclose their eyes and apply gentle pressure to the upper lid to expressthe medication across their upper and lower eyelid margins. Theformulation can then be allowed to dry without dabbing with a tissue.The formulation can then be stored at room temperature in aclimate-controlled environment (15 to 30° C.), avoiding extreme heat orcold. In some embodiments, the patient is instructed not to apply anyother topical ophthalmic medications within a specified period, e.g.,one hour before and one hour after administering the study medication.

In some embodiments, systems and methods include qualitative and/orquantitative assessment of Demodex on an anatomical location of thepatient, such as on eyelashes and/or within glands, for example. In someembodiments, a method can include receiving a first assessment of aquantity of Demodex mites on an anatomical structure of the patient andinitiating topical administration of the dermatologic and/or ophthalmiccomposition if the quantity of Demodex mites is greater than apredetermined value, such as greater than about 1, 1.5, 2, 2.5, 3, 4, 5,or more mites per square centimeter of skin (or mites per lash). In someembodiments, a method can include receiving a second assessment of aquantity of Demodex mites following therapy to quantitatively assessimprovement, and either continuing, modifying (via an increase ordecrease in dose, frequency, formulation, and the like), ordiscontinuing therapy based on the second assessment, which can beabout, no more than about, or at least about 1 day, 2 days, 3 days, 5days, 7 days, 10 days, 14 days, 21 days, 28 days, 30 days, or more orless after the first assessment. In some embodiments, the therapyresults in a reduction of about or at least about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 100% eradication of the Demodex at theanatomic location.

The presence of cylindrical dandruff, also known as cylindrical casts,are scales that form clear cuffs collaring the eyelash root, at the baseof the eyelash. Cylindrical dandruff on an eyelash is generallyconsidered pathognomonic for Demodex infestation, can be diagnosed viaepilation and viewed under a slit lamp microscope, and then countedautomatically or manually. Skin surface biopsy (SSB) technique withcyanoacrylic adhesion is a commonly used method to measure the densityof Demodex. It allows the collection of the superficial part of thehorny layer and the contents of the pilo-sebaceous follicle. Othersampling methods used in assessing the presence of Demodex by microscopyinclude adhesive bands, skin scrapings, skin impressions, expressedfollicular contents, comedone extraction, hair epilation, and punchbiopsies.

In some embodiments, systems and methods for detecting Demodex in asubject are disclosed that do not necessarily require epilation. Suchmeasures of diagnosis of Demodex can be advantageous because Demodex,particularly Demodex brevis can be challenging to detect and quantifyvia epilation. Furthermore, many patients object to epilation due todiscomfort. Furthermore, initiation of treatment could be earlier andbased on objective criteria.

For example, a device, such as a disposable hydrogel contact lens can beutilized to collect tears from a subject. This device, e.g., lens isthen sent to a laboratory for detecting, and potentially quantifying,Demodex DNA by PCR or other means. The genome for both Demodexfolliculorum and Demodex brevis have been sequenced. A “diagnostic” lenscan be placed on the eye and removed after at a short, fixed period,such as about or less than about 30, 20, 15, 10, or 5 minutes, forexample. Such a lens can made of a hydrogel with relatively highaffinity for a Demodex biomarker, including DNA.

In some embodiments, tear sampling can utilize devices includingcapillary glass tubes to harvest tears from the lower lid tear meniscusas shown in FIG. 4A. This method can be especially useful whenquantitative, small volumes are needed. In addition, evaporation can beeliminated, if beneficial to do so, simply by sealing both ends of thetube.

Some embodiments also include non-contact lens skin and tear samplingmethods, for example a “litmus paper” or wicking paper embodimentsimilar to a Schirmer test (illustrated in FIG. 4B), or a lash brushharvesting technique (illustrated in FIG. 4C). In some embodiments,chitin, chitosan, or other Demodex-specific biomarkers that could bedetected and quantified to correlate with mite numbers.

Demodex DNA can be quantified, for example, as the density of DNA copiescoding for a particular Demodex target sequence (e.g., 18S rRNA as onenon-limiting example). In some embodiments, a density (defined as thenumber of DNA copies coding for a target region of Demodex per ng ofhuman gDNA (×10⁻⁶) of Demodex can be a threshold to initiate therapy ifgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, or more.

An infestation could be further categorized as to causative species ofDemodex (e.g., Demodex folliculorum vs Demodex brevis). Demodex brevisresides mostly within the meibomian and sebaceous glands. Treatmentcould be modified, enhanced, or targeted based on the dominant species,e.g., increasing delivery of the therapeutic formulation to selectedglands, for example.

Various other modifications, adaptations, and alternative designs are ofcourse possible in light of the above teachings. Therefore, it should beunderstood at this time that within the scope of the appended claims theinvention may be practiced otherwise than as specifically describedherein. It is contemplated that various combinations or subcombinationsof the specific features and aspects of the embodiments disclosed abovemay be made and still fall within one or more of the inventions.Further, the disclosure herein of any particular feature, aspect,method, property, characteristic, quality, attribute, element, or thelike in connection with an embodiment can be used in all otherembodiments set forth herein. Accordingly, it should be understood thatvarious features and aspects of the disclosed embodiments can becombined with or substituted for one another in order to form varyingmodes of the disclosed inventions. Thus, it is intended that the scopeof the present inventions herein disclosed should not be limited by theparticular disclosed embodiments described above. Moreover, while theinvention is susceptible to various modifications, and alternativeforms, specific examples thereof have been shown in the drawings and areherein described in detail. It should be understood, however, that theinvention is not to be limited to the particular forms or methodsdisclosed, but to the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the various embodiments described and the appended claims.Any methods disclosed herein need not be performed in the order recited.The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “applying an isoxazoline parasiticide to an eye”includes “instructing the applying an isoxazoline parasiticide to aneye.” The ranges disclosed herein also encompass any and all overlap,sub-ranges, and combinations thereof. Language such as “up to,” “atleast,” “greater than,” “less than,” “between,” and the like includesthe number recited. Numbers preceded by a term such as “approximately,”“about,” and “substantially,” as used herein include the recited numbers(e.g., about 10%=10%), and also represent an amount close to the statedamount that still performs a desired function or achieves a desiredresult. For example, the terms “approximately,” “about,” and“substantially” may refer to an amount that is within less than 10% of,within less than 5% of, within less than 1% of, within less than 0.1%of, and within less than 0.01% of the stated amount.

What is claimed is:
 1. A method for treating blepharitis in a patient,comprising: topically administering directly to an ocular surface of oneor more eyes of a patient in need of treatment thereof an effectiveamount of an isoxazoline parasiticide, formulated into an ophthalmiccomposition, the ophthalmic composition further comprising apharmaceutically acceptable vehicle, wherein the ophthalmic compositionis sterile and non-irritating to the eye, wherein the isoxazolineparasiticide is the sole active ingredient of the ophthalmiccomposition.